eSOMA-DM1，一种基于Maytansinoid的小分子药物递送诊断联合治疗药物，用于神经内分泌肿瘤

背景：传统化疗的主要挑战在于其缺乏选择性和特异性，导致显著的副作用。利用小分子药物偶联物（SMDC）通过与靶向载体偶联，确保将细胞毒性药物定向递送至肿瘤部位。这一具有潜力的策略可通过选择特异性结合生长素受体亚型2（SSTR2）的靶向载体，应用于神经内分泌肿瘤（NETs）。此外，向分子中引入双功能螯合剂可以实现诊断和治疗放射性核素的复合，使得可以监测SMDC在体内的分布，并支持联合治疗。在我们的研究中，设计了eSOMA-DM1，一种结合了SSTR2靶向octreotate肽和细胞毒药物DM1的SMDC，采用螯合桥联连接（N3-Py-DOTAGA）。该方法确保在相反的两个端点连接靶向载体和药物，以避免不良的空间阻碍效应。方法：DM1部分（4）的合成采用三步法路线，随后通过无铜的点击反应将其与环肽N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH偶联，得到eSOMA-DM1。随后的[111In]InCl3标记显示出高的放射化学产率和纯度。体外在转染有SSTR2的U2OS细胞中评估了eSOMA-DM1的结合、摄取和内吞作用。在体外外的生物分布和荧光成像在H69肿瘤负载的小鼠中进行。结果：eSOMA-DM1的SSTR2半数抑制浓度（IC50）与金标准DOTA-TATE相当。在U2OS.SSTR2细胞中，[111In]In-eSOMA-DM1的摄取比[111In]In-DOTA-TATE低1.2倍。在H69异种移植小鼠中，[111In]In-eSOMA-DM1在所有时间点的肿瘤摄取均高于[111In]In-DOTA-TATE。血液循环时间延长导致[111In]In-eSOMA-DM1在肺、皮肤和心脏等高血管化组织中的积累增加。还观察到通过肾脏、肝脏和脾脏的排泄。结论：eSOMA-DM1是一种在体外表现出良好特性的NET特异性SMDC。然而，体内用[111In]In-eSOMA-DM1获得的结果提示需要调整以优化其分布。

Background: The main challenges of conventional chemotherapy lie in its lack of selectivity and specificity, leading to significant side effects. Using a small-molecule drug conjugate (SMDC) ensures specific delivery of a cytotoxic drug to the tumor site by coupling it to a targeting vector. This promising strategy can be applied to neuroendocrine tumors (NETs) by choosing a targeting vector that binds specifically to somatostatin receptor subtype 2 (SSTR2). Additionally, incorporation of a bifunctional chelate into the molecule enables complexation of both diagnostic and therapeutic radionuclides. Thus, it facilitates monitoring of the distribution of the SMDC in the body and allows for the implementation of combination therapy. In our study, we designed eSOMA-DM1, a SMDC combining the SSTR2-targeted octreotate peptide and the cytotoxic agent DM1 via a chelate-bridged linker (N3-Py-DOTAGA). This approach warrants conjugation of the targeting vector and the drug at opposite sites to avoid undesired steric hindrance effects. Methods: Synthesis of the DM1 moiety (4) involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N3-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH, through a copper-free click reaction, resulting in eSOMA-DM1. Subsequent labeling with [111In]InCl3 gave a high radiochemical yield and purity. In vitro assessments of eSOMA-DM1 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results: eSOMA-DM1 exhibited an IC50 value for SSTR2 similar to the gold standard DOTA-TATE. The uptake of [111In]In-eSOMA-DM1 in U2OS.SSTR2 cells was 1.2-fold lower than that of [111In]In-DOTA-TATE. Tumor uptake in H69-xenografted mice was higher for [111In]In-eSOMA-DM1 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eSOMA-DM1 in highly vascularized tissues, such as the lungs, skin, and heart. Excretion through the kidneys, liver, and spleen was also observed. Conclusion: eSOMA-DM1 is a SMDC developed for NET showing promising characteristics in vitro. However, the in vivo results obtained with [111In]In-eSOMA-DM1 suggest the need for adjustments to optimize its distribution.